D. Ross Camidge, MD, PhD

MET Inhibition in Non-Small Cell Lung Cancer

D. Ross Camidge, MD, PhD

Hi, I’m Ross Camidge. I’m the Director of Thoracic Oncology at the University of Colorado.

Cancer Therapy Advisor

What are some of the most promising new options for the treatment of non-small cell lung cancer (NSCLC), in your view?

D. Ross Camidge, MD, PhD

The excitement about immunotherapy, I think, is tempering because attempts to build on the efficacy of PD-1 or PD-L1 have been a little disappointing to date and, whilst everybody has a drug that they want to add in, I think the challenges is not knowing who they’re going to work in. And so there is a desperate need for personalized medicine in immunotherapy. So I guess that’s in the not exciting group.

I think we will start to see a few more targetable subgroups, oncogene driven subgroups, RET is absolutely going to get a license in 2020. MET exon 14 skip mutations almost certainly the same. And then there is a few small subgroups MET fusions, for example, some other rarer things like NRG1 fusions are continuing to be explored. And then I think we’re going to get a second wave because every one of these targeted therapies is going to develop acquired resistance. Some of them will be on target and we’ll need next generation drugs for those and some of them will be the usual suspects coming back in as second drivers, so a sort of Best Supporting Actor Oscar. And then we’re going to see a drug, let’s use a MET inhibitor as an example, that might have a role in a primary MET-driven disease but also a role in combination where MET is acting as a driver of secondary resistance, EGFR, but now we’ve also seen that in ALK, for example.

Cancer Therapy Advisor

What are the prevailing beliefs about the efficacy of immunotherapy in driver-oncogene–positive patients with NSCLC?

Dr Camidge

When we say immunotherapy, let’s be clear, we’re talking about PD-1 or PD-L1 antagonists. Certainly for many of the drive oncogene subtypes of non-small cell lung cancer, these tend to cluster in never-smokers and we know that the oncogene itself is rarely a presentable antigen and therefore the other stuff which drives the antigenicity and if you’re a never-smoker you haven’t got much other stuff going on. ALK would be a great example, there is almost not a single recorded case of an ALK patient anywhere in the world responding to immune monotherapy. Some of the other cases are smatterings and you always want to say ‘well how well did they actually get the diagnosis right,’ ‘was there something atypical about that case?’ EGFR is interesting. I think there definitely is some kind of a signal, it’s just less than with the non-driver oncogene subtypes of lung cancer and maybe we’ll be able to identify the subgroup within that subgroup of EGFR who is really benefitting.

There are some exceptions; KRAS, BRAF and MET amplification to some extent, which can occur in heavy smokers, and maybe that’s the reason why they’re breaking those rules.

I think some of the things that we’ve identified relate to immune monotherapy, but then do the same things apply to combinations with chemotherapy, KEYNOTE-189 (ClinicalTrials.gov Identifer: NCT02578680) and other studies like that excluded those with driver oncogene, so we don’t have a data set from there. From IMpower130 (ClinicalTrials.gov Identifier: NCT02367781), which was platinum taxane plus or minus atezolizumab, there was no signal in EGFR or ALK there, but it’s really only the IMpower150 (ClinicalTrials.gov Identifier: NCT02366143) which was platinum-taxane bevacizumab, plus or minus atezolizumab, that had a hint of a signal. But before you get too excited about it, the entire data set for ALK is trivial and for EGFR is barely 40 to 60 patients and remember that’s across 2 arms. Interesting enough, IMpower150, while the Euopean Medicines Agency approved their regime to include those with a driver oncogene, the US Food and Drug Administration (FDA) didn’t. So the FDA must have seen that data and said, well, no we’re actually excluding that. And the real worry, not only is it just a small subset, but you don’t know it’s balanced in terms of other risk factors. So, some people are using it off-label. I think the biggest sin is using something other than the IMpower150 off-label, like the KEYNOTE-189, that is totally data free but other studies are ongoing and hopefully we’ll actually get a better signal in the future.

Cancer Therapy Advisor

In patients with MET-expressing NSCLC, what is the role of PD-L1 positivity or negativity as it relates to treatment with immunotherapy?

Dr Camidge

I think when we say MET expressing, we have to drill down into some detail. So, expression of the protein doesn’t really mean anything. What we’re talking about is some of the genetically definable MET-driven subtypes of lung cancer and some of them are easier to define then others. So MET exon 14 skip mutations is a genetic thing that is categorical, you’ve either got it or not. MET fusion, similarly, you’ve either got it or not. MET amplification is a continuous variable that can be measured in different ways and that is very challenging to define one group within there.

But let’s talk about the ones that we do know about, and let’s focus down onto MET exon 14. One of the things we know about PD-L1 expression in those with a driver oncogene, is it can be elevated for reasons other than it being reflective of immune system primed to attack the cancer. So sometimes if you look there, there is no T-cells at all and that means it’s downstream of the oncogene and it has zero predictive value. So if you’ve got somebody who’s got a driver oncogene or someone who is a never-smoker and you have high PD-L1 levels, you should have a little red flag going “approach with caution” because this isn’t always going to say, you know, these guys need to respond to immunotherapy. The early data with MET exon 14 skip mutations was that they were not particularly immune responsive. I think, for myself, I would always try and prioritize targeting the oncogene over immunotherapy. I think, are there going to be some exceptions like in the EGFR field, maybe we just have to wait and see.

Cancer Therapy Advisor

Among the MET alterations that exist, which are associated with cancers that are the most challenging to treat: MET exon 14-skipping alterations, MET amplifications, or MET protein overexpression?

Dr Camidge

I think, at the moment, the unmet need is when we can define these oncogene-driven subtypes. For MET exon 14, there is no licensed drug, although probably there will be. MET amplification, the same, although the challenge there is how do we define within this continuous variable what is actually the relevant level of MET amplification. MET protein expression so far is a messy endpoint. I don’t think it is a primary thing you could look for, although I think there were some MET exon 14 skip mutations that don’t express the protein and are not truly oncogene driven. I think MET protein expression may come in in the future as a secondary confirmation in some of these subtypes, particularly MET exon 14 skip mutations but that is not there at present.

Cancer Therapy Advisor

What has been seen so far in terms of acquired resistance to MET inhibitors in patients with NSCLC?

Dr Camidge

When you take somebody who has a pure MET-driven cancer , so for example a MET exon 14 skip mutation, and you treat them with a MET inhibitor and they initially respond, when they develop acquired resistance the mechanism is the same as what we’ve seen in everyone else. They’re a on-target resistance mechanism so you can get MET kinase domain mutations, of which there are multiple, which have been described and presumably you will get bypass tracks. There is a kind of halfway house, we probably are seeing MET amplification as what might be an intermediate step, probably before you develop some of these MET resistance mutations, but it’s really the on-target MET mutations that we’re going to start to see described in more detail. Changing the class of MET inhibitor can actually overcome those in some situations, and bypass tracks is still a work in progress.

Cancer Therapy Advisor

Are there any other important topics that you would like to note regarding MET inhibition in NSCLC?

Dr Camidge

When we start to see data on these new MET inhibitors, let’s say MET exon 14 skip mutated non-small cell lung cancer, there’s a couple of things that I think we should bear in mind. The response rates are all running about 40% to 50%. Now we’re used to, with ALK or EGFR, response rates of much higher (70% to 80%). So what’s going on?

I think what may be going on, certainly the first clues are, there were some people with MET exon 14 who are not truly addicted, and we can see there are some people who don’t express MET protein. There are some people who have a MET exon 14 skip mutation but have an obvious other oncogenic driver, like a KRAS mutation. These are, if you like, failed attempts for from MET exon 14 to actually become a true driver and that may be bringing down the response rate to some extent. Now those are easy things that we could actually test for in the future, you get a MET exon 14 skip mutation, is there protein, yes or no? Is there another oncogenic driver, yes or no? There may be other aspects of heterogeneity going on. The reason all of that matters is when you’re trying to say “well, is this drug better than that drug,” when you’re trying to compare between studies, you don’t quite know that the same patients went in. Just as the response rate can be being diluted by people who are not truly MET driven, the progression-free survival rate can be brought down by that. And our best way, maybe, of assessing these things at the moment is looking at the duration of response, because you selected for those ones who are clearly addicted because they had a response. And assuming that the duration of follow up is the same maybe the duration response might be the only way at present that we have a saying whether one drug is actually different from the other.

The one other caveat amongst that is we are starting to understand the natural history of this disease, you do get brain metastases with MET exon 14 skip mutations. How well are these drugs at getting into the brain? How good is the central nervous system efficacy data set to allow us to compare between the drugs? All to play for.

This transcript has been edited for clarity and accuracy.